The present invention relates to a scleral plug made from a novel composition with a view to treating or preventing vitreoreti disorders.
Intraocular diseases such as diseases of a retina or vitreous body are often intractable, and a development of an effective treatment method is eagerly desired Though ocular diseases are most generally treated by installation of drugs, the drugs are hardly delivered to the in tissues such as a retina and vitreous body, rendering the treatment of the intraocular diseases all the more difficult. An attempt was made to treat the diseases by intravenous administration or the like. However, because of a blood-aqueous barrier, it is difficult to allow the drug to be delivered to attain an effective concentration. A method is known in which the drug is directly injected into the vitreous body. However, injection of a high concentration drug all at once causes damage to intraocular tissues and, moreover, it is not practical to repeat the injection because of the danger of infection and the cumbersomeness of treatment procedure.
In view of this, a scleral plug made of a biodegradable copolymer was devised (See U.S. Pat. No. 5,107,643). The scleral plug can be easily inserted into a small incision of sclera that is formed at the time of a vitreoretinal surgery. This scleral plug is formed from a poly(lactide-co-glycolide) made of lactic acid units and glycolic acid units, containing a drug, whereby the drug is gradually released into a vitreous body by utilizing the biodegradation of the copolymer in order to treat the vitreoretinal diseases.
The scleral plug is inserted into the small scleral incision formed at the time of the vitreoretinal surgery. The scleral plug needs to be strong enough not to break or chip by manipulation with tweezers during surgery. Moreover, the scleral plug needs to have properties to release a drug gradually during the desired period of time for treatment and to be degraded in ocular tissues and absorbed in the tissues afterwards. U.S. Pat. No. 5,707,643 discloses that he scleral plug is preferred to have a molecular weight (weight-average) of the copolymer of 10,000 to 1,000,000 and proposes that lactic acid and glycolic acid are used in an appropriate copolymenzation ratio making the most of both characteristics. However, there was still room for improvement in the scleral plug made from the poly(lactide-co-glycolide) in terms of the sustained drug release. Namely, when the drug is required to be gradually released over a long period of time, a hydrolysis rate of the plug is designed to be slow. Accordingly, the resulting oligomers and monomers owing to the hydrolysis are not released out of matrix smoothly, and they are gradually accumulating in the matrix. Consequently, it is feared that the inner osmotic pressure increases gradually and the drug is released at a time accompanied by disintegration of the plug. Accordingly, it is not easy to release the drug accurately in a constant amount to the end, and improvement of the plug was required
As a result of precise studies of improvement of this scleral plug, the present inventors found that the above-mentioned problem can be solved by combining a high-molecular weight polylactic acid with a low-molecular weight polylactic acid in a suitable ratio and blending them.
The scleral plug is characterized by being formed from a blend of the high-molecular weight polylactic acid and the low-molecular weight polylactic acid First, the low-molecular weight polylactic acid, which is apt to be hydrolyzed, degrades in vivo gradually and begins to release a drug gradually, and the whole plug changes into porous structure gradually. Next, the high-molecular weight polylactic acid, which is hardly hydrolyzed, degrades gradually. The release of the drug can be controlled to be constant until the plug disintegrates, since the resulting oligomers and monomers owing to hydrolysis are smoothly released through the porous structure out of matrix.
The high-molecular weight polylactic acid means polylactic acid having a molecular weight (weight-average, the same definition is applied hereinafter) of 40,000 or higher. The low-molecular weight polylactic acid means polylactic acid having a molecular weight of 40,000 or lower. However, polylactic acid having a mole weight of 40,000 is not used as the high-molecular weight polylactic acid and the low-molecular weight polylactic acid at the same time. It is not particularly necessary to define the upper limit of the molecular weight of the high-molecular weigh polylactic acid, but the molecular weight is practically 1,000,000 or lower, considering a releasing period of the drug, that is, a degradation rate of the plug. The lower limit of the molecular weight of the low-molecular weight polylactic acid is not also particularly limited, but the molecular weight is practically 3,000 or higher, considering a releasing rate of the drug. The release of the drug can be controlled by appropriately selecting each molecular weight of the high-molecular weight polylactic acid and the low-molecular weight polylactic acid used, and a blending ratio thereof.
When it is necessary to release the drug over a long period of time, the scleral plug of the present invention is particularly suitably used. The releasing period can be determined mainly on the basis of the molecular weight of the high-molecular weight polylactic acid used. For example, when a high-molecular weight polylactic acid having a molecular weight of 100,000 to 200,000 is used as a major component, the releasing period can be adjusted to about half a year to one year. When a high-molecular weight polylactic acid having a molecular weight of 40,000 to 100,000 is used as a major component, the releasing period can be adjusted to about several weeks to half a year When a high-molecular weight polylactic acid having a molecular weight of 200,000 or higher is wed, the plug can have longer-term releasing persistence. The molecular weight of the high-molecular weight polylactic acid is selected considering a possible content and an effective concentration of the drug
A main role of the low-molecular weight polylactic acid is to make the plug porous and to control the release amount of the drug to be constant. This effect depends on mainly a blending ratio of the low-molecular weight polylactic acid When the blending ratio of the low-molecular weight polylactic acid is too high, an initial releasing rate of the drug is high, and it is difficult to keep the release of the drug constant over a long period of time. On the contrary, when the blending ratio is too low, it is feared that the porous structure is not formed well, the resulting oligomers and the monomers owing to the hydrolysis arc not released smoothly, the plug decomposes at a time in a final stage of the release of the drugs, and the drug is also released at a time. Accordingly, the blending ratio of the high-molecular weight polylactic acid and the low-molecular weight polylactic acid is usually about 90110 to about 50150, preferably about 90/10 to about 70/30, most preferably about 80120.
The releasing period of the drug and an amount of the drug to be released are basically controlled to be constant by the molecular weight of the high-molecular weight polylactic acid and the blending ratio of the low-molecular weight polylactic acid. However, the releasing period of the drug depends on the molecular weight of the low-molecular weight polylactic acid, too. When the molecular weight of the low-molecular weight polylactic acid is decreased, the releasing rate of the drug becomes a little MO. On the contrary, when the molecular weight is increased, the releasing rate of the drug becomes a little low. Accordingly, the molecular weight of the low-molecular weight polylactic acid adjusts the releasing period finely. The molecular weight of the low-molecular weight polylactic acid can appropriately be changed depending on the desired releasing period. The molecular weight is selected usually in the range of 3,000 to 40,000, more preferably in the range of 5,000 to 20,000.
As regards physical strength, which is a requirement of the scleral plug, the molecular weight of the polymer can be 10,000 or higher. When the high-molecular weight polylactic acid having the molecular weight of 40,000 or higher is used as a major component like the present invention, the scleral plug maintains sufficient strength.
The polylactic acid can be a DL-, L- or D-form, and it is preferable to use the DL- or L-form.
The scleral plug can have essentially the same shape and size as those disclosed in U.S. Pat. No. 5,707,643, that is, a nail-like shape comprising a head portion and a shaft portion. The end of the shaft portion can be formed in an acute-angled shape.
The scleral plug is used for treatment or prevention of various vitreoretinal diseases. Examples of specific diseases are viral or bacterial infections, proliferative vitreoretinopathy accompanied by proliferation of new blood vessels or real cells, retinal hemorrhage, retinal detachment or retinoblastoma due to various causes or the like. The drug to be contained in the scleral plug is not limited and can be selected depending on the diseases. For example, for treatment of viral infections, antiviral agents such as ganciclovir are used. Doxorubicin hydrochloride, etc. are used for treating proliferative vitreoretinopathy. Content of the drug can appropriately be adjusted depending on the kinds, the necessary effective concentrations and the releasing periods of the drug, symptoms, etc. For example, the Content of ganciclovir is usually 1 to 4 mg, preferably 1.5 to 2.5 mg. The weight of the scleral plug of the present invention is about 8 to 10 mg, and the drug content is determined considering balance of a sustained release effect and an amount required for the treatment.
A plurality of the scleral plugs of the present invention can be used simultaneously. When the scleral plug becomes unable to maintain the effective concentration of the drug, it can be replaced with a new one.
Particular techniques are not required for producing the scleral plug of the present invention For example, the scleral plug is obtained by dissolving the high-molecular weight polylactic acid, the low-molecular weight polylactic acid and the drug in a certain amount of a solvent such as acetic acid, lyophilizing the solution and then forming plugs out of the obtained powder